Cyclin-dependent kinase 5 (CDK5) is a key player that governs brain development and function by phosphorylation of serine and threonine residues on diverse protein targets. Unlike other CDK members, CDK5 does not control normal cell cycle progression, but plays prominent roles in controlling neuronal migration, dendritic spine density, neurotransmitter receptor signaling, and activity-dependent synaptic plasticity in post-mitotic brain neurons. Moreover, dysregulation of CDK5 is reported in an increasing list of brain disorders, including Alzheimer's disease, schizophrenia, stroke, and epilepsy. Activation of CDK5 depends on the available amount of p35 or p39, two non-cyclin activators encoded by the CDK5R1 and CDK5R2 gene, respectively. Previous studies have overwhelmingly focused on the function of p35 in controlling CDK5 signaling, partly due to the severe phenotype of p35-/- mice in embryonic brain development and the involvement of p35 in neurotoxic damage. Why postnatal brain neurons express abundant p39 is not understood and unfortunately understudied. Importantly, emerging evidence has revealed differential functions of p35 and p39 in normal and diseased brains. However, molecular mechanisms that regulate CDK5 activator expression in neurons, which in turn govern CDK5 activity, are vastly unknown. In particular, which CDK5 activator is responsible for modulating CDK5 activity and promoting neuronal and synapse development is undefined. Moreover, whether and how neuronal activation regulates CDK5 activator expression thus underlie CDK5-dependent brain function is an intriguing question that remains to be answered. This proposal focuses on elucidating the regulation and function of the CDK5R2 gene that encodes p39. Based on our preliminary data, we hypothesize that selective regulation of p39 is responsible for modulating CDK5 activity during neuronal differentiation and activation, which directs CDK5 signaling toward specific targets to control synaptic development and brain function in response to physiological and pathological challenges. We propose the following Specific Aims to test this hypothesis: (1) To determine molecular mechanisms that regulate p39 expression during neuronal development and in response to neuronal activity changes; (2) to determine the function and targets of p39 in CDK5 signaling and dendritic spine/synapse development; (3) To determine the role of p39 in learning and memory formation and epileptogenesis.